The present invention relates to new tricyclic compounds, their preparation process and the intermediates of this process, their use as medicaments and the pharmaceutical compositions containing them.
A subject of the present invention is the compounds of general formula (I): 
in which R1 represents a xe2x80x94Cxe2x89xa1Cxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6, xe2x80x94CHxe2x95x90CHxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6, xe2x80x94(CH2)2xe2x80x94[A]xe2x80x94[B]xe2x80x94COR6, xe2x80x94Oxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6, xe2x80x94CH2COxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6 group, xe2x80x94[A]xe2x80x94 representing
either a bivalent hydrocarbonated radical derived from a saturated or unsaturated, linear or branched structure containing 1 to 12 carbon atoms and 1 to 6 heteroatoms chosen from oxygen, nitrogen or sulphur atoms,
or a bivalent radical derived from a saturated or unsaturated, linear or branched acyclic hydrocarbon containing 1 to 12 carbon atoms,
[B] representing a phenyl radical, a CH[Z] radical, or a single bond,
Z represents a hydrogen atom, one of the following groups:
(D)0-6xe2x80x94NRaRb, (D)0-6xe2x80x94NHxe2x80x94SO2xe2x80x94Rc, (D)0-6xe2x80x94NHxe2x80x94CO2xe2x80x94Rc, (D)0-6xe2x80x94NHxe2x80x94COxe2x80x94Rc, (D)0-6xe2x80x94NHxe2x80x94SO2xe2x80x94NHxe2x80x94Rc, (D)0-6xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94Rc, (D)0-6xe2x80x94CO2xe2x80x94Rc, (D)0-6xe2x80x94SO2xe2x80x94Rc, (D)0-6xe2x80x94CO-Rc or (D)0-6xe2x80x94Rc in which (D)0-6 is a bivalent radical derived from a saturated or unsaturated, linear or branched acyclic hydrocarbon containing 0 to 6 carbon atoms,
Ra, Rb and Rc represent a hydrogen atom, a (CH2)0-3xe2x80x94Ar radical in which Ar represents a carbocyclic aryl group containing 6 to 18 carbon atoms, a (CH2)0-3-Het radical in which Het represents a radical derived from a saturated or unsaturated, aromatic or non-aromatic heterocycle containing 1 to 9 carbon atoms and 1 to 5 heteroatoms chosen from oxygen, nitrogen or sulphur atoms, a (CH2)0-3-Alk radical in which Alk represents a radical derived from a saturated or unsaturated, linear, branched or cyclic, non-aromatic hydrocarbon, containing 1 to 12 carbon atoms, the Het, Ar and Alk radicals being able to be non-substituted or substituted, or also, Ra and Rb represent together with the nitrogen atom to which they are linked a saturated or unsaturated, aromatic or non-aromatic, nitrogenous heterocycle optionally containing one or more heteroatoms chosen from oxygen, nitrogen or sulphur atoms, this radical being able to be substituted or non-substituted,
R6 represents a hydroxyl radical, an O-Alk Oxe2x80x94Ar, NH2 NH-Alk, N(Alk)2 radical or the remainder of a L or D amino acid, Alk and Ar being as defined previously and being optionally substituted or not substituted,
R2 and R3, identical or different, represent either a hydrogen atom, a hydroxyl radical, an O-Alk radical or an Oxe2x80x94(CH2)0-3xe2x80x94Ar radical, Alk and Ar being as defined previously, or R2 and R3 form together with a ring of xe2x80x94Oxe2x80x94(CRdRe)nxe2x80x94 type, n being an integer from 1 to 5, Rd and Re independently of each other represent a hydrogen atom, an alkyl radical containing 1 to 6 carbon atoms, or a phenyl radical,
R4 represents a hydrogen atom, a halogen atom, one of the following groups: hydroxyl, amino, nitro, cyano, CF3, acyl or acyloxy containing 1 to 12 carbon atoms, alkyl, alkenyl, alkynyl, alkylthio, alkoxy, alkylamino, dialkylamino, dialkylaminoalkyl, dialkylaminoalkyloxy, in which the term alkyl contains 1 to 6 carbon atoms,
R5 represents a hydrogen atom, a hydroxyl radical, a halogen atom, an O-Alk radical or an Oxe2x80x94(CH2)0-3xe2x80x94Ar radical, Alk and Ar being as defined previously,
G represents,
either a radical of formula G1 
in which Rh is a hydrogen atom or an (Alk) group as defined previously and (Hetxe2x80x2) is a heterocycle of general formula: 
in which (H) forms, with the Nxe2x95x90Cxe2x80x94NHxe2x80x94 unit, the remainder of a saturated or unsaturated, mono- or bicyclic, aromatic or non-aromatic heterocycle containing 1 to 9 carbon atoms and 2 to 5 heteroatoms chosen from oxygen, nitrogen and sulphur atoms, this radical being able to be substituted or non-substituted,
or an NRaRb radical (radical G2), Ra and Rb being as defined above,
or a (Het) radical (radical G3) as defined above,
or an xe2x80x94NRhxe2x80x94C(xe2x95x90X)xe2x80x94NHRc radical (radical G4), in which X is a sulphur or oxygen atom or NH, Rh and Rc are as defined previously,
or an xe2x80x94NRhxe2x80x94SO2Rc radical, (radical G5), in which Rh and Rc are as defined previously, the dotted lines represent an optional second bond, as well as the addition salts with acids and bases and the esters. R1, R2 and R3 can be in position 8, 9 or 10 of the tricycle.
By compound of formula (I) is meant all the possible geometrical isomers and stereoisomers taken individually or as a mixture.
By xe2x80x94[A]xe2x80x94 group representing a bivalent radical derived from a saturated or unsaturated, linear or branched structure containing 1 to 12 carbon atoms and 1 to 6 heteroatoms chosen from oxygen, nitrogen and sulphur atoms, is meant in particular, radicals derived from the alkanes some of whose carbons are replaced by oxygen or sulphur atoms, or by the following groups: Cxe2x95x90O, SO, SO2, NH, N(Alk), NHxe2x80x94CO, N(Alk)xe2x80x94CO, COxe2x80x94NH, COxe2x80x94N(Alk), SO2xe2x80x94NH, SO2xe2x80x94N(Alk), (Alk) being as defined above. It can therefore be the following radicals:
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94CH2xe2x80x94CH2xe2x80x94, CH2xe2x80x94CH2xe2x80x94C(O)xe2x80x94CH2xe2x80x94CH2, CH2xe2x80x94C(O)xe2x80x94C(Me)2xe2x80x94CH2.
When xe2x80x94[A]xe2x80x94 represents a bivalent radical derived from a saturated or unsaturated, linear or branched, acyclic hydrocarbon containing 1 to 12 carbon atoms, there are meant in particular the alkylene radicals of formula xe2x80x94(CH2)nxe2x80x94, in which n represents an integer comprised between 1 and 12, such as xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, or the alkenylene or alkynylene radicals such as xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 or xe2x80x94Cxe2x95x90Cxe2x80x94CH2xe2x80x94.
When these bivalent radicals are branched, they can be radicals such as xe2x80x94CH(CH3)xe2x80x94; xe2x80x94C(Me)2, xe2x80x94CH2xe2x80x94C(Me)2xe2x80x94, xe2x80x94CH(Et)xe2x80x94, xe2x80x94CH(Cxe2x95x90CH)xe2x80x94 or xe2x80x94C(Cxe2x89xa1CH)(Et)xe2x80x94.
When [B] represents a xe2x80x94Phxe2x80x94 bivalent radical, the COR6 group can be in ortho, meta or para position. It is preferably found in the para position.
When (D)0-6 is a bivalent radical derived from a saturated or unsaturated, linear or branched, acyclic hydrocarbon containing 0 to 6 carbon atoms, (D)0-6 is chosen from the values of [A] mentioned above. By (D)0 is meant the absence of this radical which once again has a single covalent bond. (D) will preferably be a single bond or a (CH2)n group, n being an integer chosen from 1, 2 or 3.
When Ra, Rb and Rc represent a (CH2)0-3xe2x80x94Ar, (CH2)0-3-Het, (CH2)0 3-Alk group, (CH2)0-3 represents either a single bond in the case of (CH2)0, or the radical xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)3xe2x80x94.
By the term (Ar) representing a carbocyclic aryl group containing 6 to 18 carbon atoms is meant a radical derived from an aromatic cyclic hydrocarbon such as the phenyl, naphthyl, phenanthrenyl radical or a radical derived from a condensed bicyclic or tricyclic hydrocarbon containing a benzene ring such as indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl. The junction occurs at the level of the benzene ring. It is preferably the phenyl.
By the term (Het) representing a radical derived from a saturated or unsaturated, aromatic or non-aromatic heterocycle containing 1 to 9 carbon atoms and 1 to 5 heteroatoms chosen from oxygen, nitrogen and sulphur atoms, is meant in particular:
monocyclic heterocyclic radicals, for example the following radicals: thienyl, furyl, pyrannyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazannyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl,
condensed heterocyclic rings, for example benzofurannyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho[2,3-b]thienyl, thianthrenyl, isobenzofurannyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl or also the condensed polycyclic systems constituted by monocyclic heterocyclic radicals as defined such as for example furo[2,3-b]pyrrole or thieno[2,3-b]furan,
or saturated heterocyclic radicals such as pyrrolidine, piperidine, morpholine.
This term (Het) includes furthermore the values of (Hetxe2x80x2) as defined previously.
By the term (Alk) representing a radical derived from a saturated or unsaturated, linear, branched or cyclic, non-aromatic hydrocarbon, is meant in the case of acyclic hydrocarbons the alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethyl pentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl, 2,4-dimethylheptyl or n-decyl, the alkenyl radicals such as vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl, or the alkynyl radicals such as ethynyl, propynyl, propargyl, butynyl or isobutynyl, and in the case of the cyclic radicals, the cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.
When Ra and Rb represent together with the nitrogen atom to which they are linked a nitrogenous heterocycle, they are in particular the following saturated heterocycles: morpholine, piperidine, piperazine, pyrrolidine, or the unsaturated heterocycles such as pyrimidine, pyridine or pyrazine.
When R2, R3, R4 and R5 represent an O-(Alk) radical containing 1 to 12 carbon atoms, they are preferably methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, allenyloxy or propargyloxy. When R2, R3, R4 and R5 represent an Oxe2x80x94(CH2)0-3xe2x80x94Ar radical they are preferably the phenylethoxy and phenylpropyloxy radicals.
When R2 and R3 form together a ring of xe2x80x94Oxe2x80x94(CRdRe)nxe2x80x94Oxe2x80x94 type, n being an integer from 1 to 5, it is in particular the xe2x80x94Oxe2x80x94CH2xe2x80x94O, Oxe2x80x94C(Me2)xe2x80x94O, Oxe2x80x94C(Ph2)xe2x80x94O radicals. R2 and R3 must each be in ortho position.
When R6 represents an O-Alk or O-Ar radical, Alk and Ar being substituted or non-substituted, it is in particular one of the following radicals: (C1-C8)alkoxy, (C1-C14)aryl, (C1-C8)alkoxy, (C6-C14)aryloxy, (C1-C8)alkylcarboxyloxy, (C1-C8)dialkylaminocarbonylmethoxy, (C6-C14)aryl, (C1-C8)dialkyl-aminocarbonylmethoxy.
When R6 represents an NH-alk, NH(alk)2 or NHxe2x80x94Ar radical, it is in particular one of the following radicals: (C1-C8)alkylamino, di-(C1-C8)alkylamino, (C6-C14)aryl, (C2-C8)alkylamino, (C6-C14)arylamino.
When R6 represents the remainder of an amino acid it can be an L or D amino acid.
The L or D amino acids can be natural or non-natural. They are preferably xcex1-amino acids. For example, those described in Houben-Weyl, Methoden der organischen Chemie, Volume XV/1 and 2, Georg Thieme Verlag, Stuttgart, 1974: Aad, Abu, xcex3Abu, Abz, 2Abz, xcex5Aca, Ach, Acp, Adpd, Ahb, Aib, xcex2Aib, Ala, xcex2Ala, xcex94Ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hlle, hLeu, hLys, hMet, hphe, hpro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, xcex2Lys, xcex94lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, xcex94pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, xcex2Thi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, tert-butylglycine (Tbg), Neopentylglycine (Npg), Cyclohexylglycine (Chg), Cyclohexylalanine (Cha), 2-Thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2-(p-tolyl) 2-phenylamino acetic acid, 2-(p-chlorophenyl) amino acetic acid, or also 2-pyrrolidine acetic acid, 1,2,3,4-tetrahydroisoquinoline 3-acetic acid, decahydroisoquinoline 3-acetic acid, octahydroisoindol 2-acetic acid, decahydroquinoline 2-acetic acid, octahydrocyclopenta[b}pyrrol 2-carboxylic acid, 2-azabicyclo[2,2,2]octan-3-carboxylic acid, 2-azabicyclo[2,2,1]heptan-3-carboxylic acid, 2-azabicyclo[3,1,0]hexan-3-carboxylic acid, 2-azaspiro[4,4]nonan-3-carboxylic acid, 2-azaspiro[4,5]decan-3-carboxylic acid, spiro (bicyclo[2,2,1]heptan)-2,3-pyrrolidin-5-carboxylic acid, spiro (bicyclo[2,2,2]octan)-2,3-pyrrolidin-5-carboxylic acid, 2-azatricyclo[4,3,0,16,9]decan-3-carboxylic acid, decahydrocyclohepta[b]pyrrol-2-carboxylic acid, decahydrocycloocta[c]pyrrol-2-carboxylic acid, octahydrocyclopenta[c]pyrrol-2-carboxylic acid, octahydroisoindol-1-carboxylic acid, 2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrol-2-carboxylic acid, 2,3,3a,4,5,7a-hexahydroindol-2-carboxylic acid, tetrahydrothiazol-4-carboxylic acid, isoxazolidin-3-carboxylic acid, pyrazolidin-3-carboxylic acid, hydroxypyrrolidin-2-carboxylic acid, which if appropriate, can be substituted (see the following formulae): 
The heterocyclic remainders as described above are known for example from the following Patents or Patent Applications:
U.S. Pat. No. 4,344,949; U.S. Pat. No. 4,374,847; U.S. Pat. No. 4,350,704; EP-A-29,488; EP-A-31,741; EP-A-46,953; EP-A-49,605; EP-A-49,658; EP-A-50,800; EP-A-51,020; EP-A-52,870; EP-A-79,022; EP-A-84,164; EP-A-89,637; EP-A-90,341; EP-A-90,362; EP-A-105,102; EP-A-109,020; EP-A-111,873; EP-A-271,865 and EP-A-344,682.
In addition the amino acid can be in ester or amide form, such as for example, methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester, ethylamide, semicarbazide or xcfx89-amino (C2-C8)-alkylamide.
Finally, the functional groups of these amino acids can be protected. Suitable protective groups such as urethane protective groups, carboxyl protective groups or side-chain protective groups are described by Hubbuch, Kontakte (Merck) 1979, No 3, p. 14-23 and by Bxc3xcllesbach, Kontakte (Merck) 1980, No 1, p. 23-35.
For example, the following can be mentioned: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO2), Z(Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tertbutyl, Obzl, Onbzl, Ombzl, Bzl, Mob, Pic, Trt.
When G is a radical of formula G1 
and (Hetxe2x80x2) is a heterocycle of general formula: 
in which (H) forms, with the Nxe2x95x90Cxe2x80x94NHxe2x80x94 unit, a saturated or unsaturated, mono- or bicyclic, aromatic or non-aromatic heterocycle containing 1 to 9 carbon atoms and 2 to 5 heteroatoms chosen from oxygen, nitrogen and sulphur atoms, this radical being able to be substituted or non-substituted, G1 represents in particular the following heterocycles: 
in which p represents an integer from 1 to 4.
When G is an xe2x80x94NRaRb radical (called G2), Ra and Rb can be a hydrogen atom, a (CH2)0-3xe2x80x94Ar, (CH2)0-3-Het or (CH2)0-3-Alk radical. The Ar, Het and Alk groups also being able to be substituted by groups as defined below.
G2 can be in particular an NH2, NH-Alk group such as NHMe, NHeT, N(Alk)2 group such as NMe2, NEt2, NMeEt, NHxe2x80x94(CH2)0-1xe2x80x94Ar group such as NHPh, NHCH2Ph or NHCH2Het group such as NHCH2-pyrrol-2-yl.
When Ra is a hydrogen atom or an (Alk) group and when Rb is a (Hetxe2x80x2) group the values of G1 are found.
When Ra and Rb form together with the nitrogen atom to which they are linked a nitrogenous heterocycle, it is in particular the heterocyclic groups as described above, these being able to be substituted or non-substituted.
When G is a (Het) radical (radical G3) this radical being able to be substituted or non-substituted, it is in particular the heterocycles listed above and especially the heterocycles of general formula (Hetxe2x80x2) as defined above. When this heterocycle is connected at the level of its nitrogen atom, the values of G2 are found in which Ra and Rb form a heterocycle with the nitrogen atom that carries them.
When G is an xe2x80x94NRhxe2x80x94C(xe2x95x90X)xe2x80x94NHRc radical (radical G4), or an NRhSO2Rc radical (radical G5), in which X is a sulphur or oxygen atom or NH, Rh and Rc are as defined previously, it is in particular one of the following groups: xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90S)xe2x80x94NH2, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHCH2xe2x80x94Ar such as xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHCH2Ph, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHCH2-Het, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHCH2-Hetxe2x80x2, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH-Alk such as xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHCH3, or xe2x80x94NHxe2x80x94SO2Ph, the Ar, Het, Hetxe2x80x2 or Alk groups being substituted or non-substituted.
The possible substituents of the (Alk), (Ar), (Het), (Hetxe2x80x2) or NRaRb radicals forming a heterocycle, are preferably the following radicals:
halogen: fluorine, chlorine, bromine, iodine,
alkyl, alkenyl, alkynyl containing 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl or allenyl; these radicals themselves being optionally substituted by one or more halogen atoms, for example fluorine such as trifluoromethyl,
oxo, cyano, nitro, formyl, carboxy and carboxyalkyl containing 1 to 6 carbon atoms, carboxamide,
alkoxy containing 1 to 12 carbon atoms such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy,
alkylthio containing 1 to 12 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,
amino, alkylamino containing 1 to 12 carbon atoms such as methylamino or ethylamino, dialkylamino containing 2 to 24 carbon atoms such as dimethylamino, diethylamino, methylethylamino, each of these dialkylamino radicals optionally being in oxidized form,
aminoalkyl containing 1 to 12 carbon atoms such as aminomethyl or aminoethyl,
dialkylaminoalkyl containing 3 to 25 carbon atoms such as dimethylamino methyl or ethyl,
dialkylaminoalkyloxy containing 3 to 25 carbon atoms such as dimethylaminoethyloxy,
optionally acylated hydroxyl containing 1 to 12 carbon atoms, for example acetoxy,
acyl containing 1 to 12 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, succinyl, pivaloyl, benzoyl optionally substituted for example by a chlorine, iodine or fluorine atom; the chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl radicals can be mentioned,
carbocyclic or heterocyclic aryl such as phenyl, furyl, thienyl, pyridinyl or aralkyl such as benzyl, these radicals themselves being optionally substituted by halogen, alkyl, alkoxy, alkylthio, amino alkyl or dialkylamino indicated above.
Of course, one or more identical or different substituents can be present. In the case of (Het) the substituents can be at the level of the NH group or the carbon atom.
These substituents also illustrate the definition of R4.
It is understood that when R1, R2, R3, R4, R5, R6, Ra, Rb, Rc contain an alkyl, aryl or heterocyclic group as defined above, they can be identical or different independently of each other.
The invention naturally extends to the salts of the compounds of formula (I), such as for example the salts formed when the compounds of formula (I) contain an amino or amino guanidine function, with the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, trifluoroacetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic such as methane- or ethanesulphonic, arenesulphonic, such as benzene or paratoluene sulphonic and arylcarboxylic, or when the compounds of formula (I) contain an acid function, with alkali metal or alkaline-earth salts or optionally substituted ammonium salts.
The invention also extends to the esters of the compounds of formula (I).
In a first preferred group, a subject of the invention is the compounds of general formula (I) as defined previously, corresponding to general formula (Ixe2x80x2): 
in which Rxe2x80x21 represents one of the following groups:
xe2x80x94Cxe2x95x90Cxe2x80x94[Axe2x80x2]xe2x80x94[Bxe2x80x2)xe2x80x94CORxe2x80x26, xe2x80x94CHxe2x95x90CHxe2x80x94[Axe2x80x2]xe2x80x94[Bxe2x80x2]xe2x80x94CORxe2x80x26, xe2x80x94(CH2)2xe2x80x94[Axe2x80x2]xe2x80x94[Bxe2x80x2]xe2x80x94CORxe2x80x26, xe2x80x94Oxe2x80x94[Axe2x80x2]xe2x80x94[Bxe2x80x2]xe2x80x94CORxe2x80x26, xe2x80x94CH2COxe2x80x94[Axe2x80x2]xe2x80x94[B]xe2x80x94CORxe2x80x26, xe2x80x94[Axe2x80x2]xe2x80x94 representing a bivalent alkylene, alkenylene or alkynylene radical containing 1 to 6 carbon atoms, [Bxe2x80x2] representing a CH(Zxe2x80x2) radical or a single bond,
Zxe2x80x2 represents a hydrogen atom, one of the following groups:
(CH2)0-6xe2x80x94NRaRb, (CH2)0-6xe2x80x94NHxe2x80x94SO2xe2x80x94Rc, (CH2)0-6xe2x80x94NHxe2x80x94CO2xe2x80x94Rc, (CH2)0-6xe2x80x94NHxe2x80x94COxe2x80x94Rc, (CH2)0-6xe2x80x94NHxe2x80x94SO2xe2x80x94NHxe2x80x94Rc, (CH2)0-6xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94Rc, (CH2)0-6xe2x80x94CO2xe2x80x94Rc, (CH2)0-6xe2x80x94SO2xe2x80x94Rc, (CH2)0-6xe2x80x94COxe2x80x94Rc or (CH2)0-6xe2x80x94Rc, Ra, Rb and Rc being as defined previously, Rxe2x80x26 represents an OH, amino or alkoxy radical containing 1 to 8 carbon atoms, optionally substituted by one or more radicals chosen from hydroxy, amino, phenyl, alkylamino or dialkylamino radicals,
Rxe2x80x22 and Rxe2x80x23 represent a hydrogen atom or a methoxy radical, and G is as defined previously, the dotted lines represent an optional second bond, as well as the addition salts with acids and bases and esters.
In a second preferred group a subject of the invention is the compounds of general formula (I) as defined previously in which R6 represents one of the following groups: xe2x80x94OH, xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94Oxe2x80x94(CH2)2xe2x80x94OH, 
xe2x80x94Oxe2x80x94(CH2)2xe2x80x94NH2, xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Nxe2x80x94(CH3)2, xe2x80x94NH2 or xe2x80x94Oxe2x80x94(CH2)-phenyl, as well as the addition salts with acids and bases and esters.
In a third preferred group a subject of the invention is the compounds of general formula (I) as defined previously in which R1 represents an Oxe2x80x94(CH2)0-6CH(Zxe2x80x2)xe2x80x94COOH or xe2x80x94(CH2)0-7xe2x80x94CH(Zxe2x80x2)xe2x80x94COOH group, as well as the addition salts with acids and bases and the esters.
In a fourth preferred group a subject of the invention is the compounds of general formula (I) as defined previously, in which (Zxe2x80x2) is a hydrogen atom, as well as the addition salts with acids and bases and the esters.
In a fifth preferred variant a subject of the invention is the compounds of general formula (I) as defined previously, in which (Zxe2x80x2) is the (CH2)0-6xe2x80x94NHxe2x80x94CO2xe2x80x94Rc or (CH2)0-6xe2x80x94NHRb group, Rb and Rc being as defined previously, as well as the addition salts with acids and bases and the esters.
In a sixth preferred group a subject of the invention is the compounds of general formula (I) as defined previously, in which Rb and Rc represent the (CH2)0-3xe2x80x94Ar group, Ar being as defined previously and being able to be substituted or non-substituted, as well as the addition salts with acids and bases and the esters.
In a seventh preferred group a subject of the invention is the compounds of general formula (I) as defined previously, in which G is a G4 group of formula xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHRc, Rc being as defined previously, as well as the addition salts with acids and bases and the esters.
In a eighth preferred group a subject of the invention is the compounds of general formula (I) as defined previously, in which G is a G4 group of formula NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2, as well as the addition salts with acids and bases and the esters.
In an ninth preferred group a subject of the invention is the compounds of general formula (I) as defined previously, in which G is an xe2x80x94NH-Hetxe2x80x2 group as defined previously and in particular 
p being an integer equal to 2, 3 or 4, these heterocycles being substituted or non-substituted, as well as the addition salts with acids and bases and the esters.
In a tenth preferred group, a subject of the invention is the compounds of general formula (I) as defined previously, in which G is the group 
p being an integer equal to 2, 3 or 4, as well as the addition salts with acids and bases and the esters.
In an eleventh preferred group, a subject of the invention is the compounds of formula (I) as defined previously the names of which follow:
4-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulen-yl)oxy)-butanoic acid,
5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulen-yl)oxy)-pentanoic acid,
5-((4-((aminoiminomethyl)hydrazono)-8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz(e)azulen-yl)oxy)-pentanoic acid,
6-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-hexanoic acid,
7-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-heptanoic acid,
5-((9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-8-benz(e)azulenyl)oxy)-pentanoic acid,
ethyl 5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoate hydrochloride,
4-((4-((aminoiminomethyl)hydrazono)-8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz(e)azulenyl)oxy)-butanoic acid,
5-((4-((aminoiminomethyl)hydrazono)-8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz(e)azulenyl)oxy)-pentanoic acid,
5-((4-(((amino)carbonyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoic acid,
5-((4-(((amino)thiocarbonyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoic acid,
4-((4-((aminoiminomethyl)hydrazono)-8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz(e)azulenyl)oxy)-butanoic acid,
6-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-hexanoic acid,
5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-3,3-dimethyl-4-oxo-pentanoic acid,
5-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-3,3-dimethyl-4-oxo-pentanoic acid,
5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoic acid hydrochloride,
4-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-butanoic acid,
5-((8-((aminoiminomethyl)hydrazono)-6,7,8,9,10,11-hexahydro-azuleno(5,6-d)-1,3-benzodioxol-4-yl)oxy)-pentanoic acid,
5-((8-((aminoiminomethyl)hydrazono)-2,2-diphenyl-6,7,8,9,10,11-hexahydro-azuleno(4,5-e)-(1,3)-benzodioxol-4-yl)oxy)-pentanoic acid,
4-((9,10-dimethoxy-4-((1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-butanoic acid,
2-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-ethanoic acid,
3-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-propanoic acid,
4-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-butanoic acid,
4-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-butanoic acid,
O-[4[(4,5-dihydro-1H-imidazol-2-yl)hydrazono]-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz[e]azulenyl]-N-[(phenylmethoxy)carbonyl]-DL-homoserine,
O-[4[(4,5-dihydro-1H-imidazol-2-yl)hydrazono]-1,2,3,4,5,6-hexahydro-8-benz[e]azulenyl]-N-[(phenylmethoxy)carbonyl]-DL-homoserine,
O-[4-[(1,2,3,4-tetrahydro6-pyrimidinyl)hydrazono]9,10-dimethoxy 1,2,3,4,5,6-hexahydro8-benz[e]azulenyl]N-[(phenylmethoxy)carbonyl]DL-homoserine,
(2,3-dihydroxypropyl) ester of O-(9,10-dimethoxy 1,2,3,4,5,6-hexahydro4-[(1,4,5,6-tetrahydro2-pyrimidinyl) hydrazono]]-8-benz(e)azulenyl)N-[(phenylmethoxy)carbonyl]DL-homoserine,
O-[4-[(4,5-dihydro1H-imidazol-2-yl)hydrazono]9,10-dimethoxy 1,2,3,4,5,6-hexahydro8-benz(e)azulenyl]N-[(8-quinolinyl)sulphonyl]DL-homoserine,
monohydrochloride of O-[4-[(4,5-dihydro1H-imidazol-2-yl) hydrazono]9,10-dimethoxy1,2,3,4,5,6-hexahydro8-benz(e)-azulenyl]N-[[3-(4-(3-pyridinyl)1H-imidazol-1-yl]propoxy]carbonyl]DL-homoserine,
5-[[4-[(4,5-dihydro4-oxo 1H-imidazol-2-yl)hydrazono]9,10-dimethoxy 1,2,3,4,5,6-hexahydro8-benz(e)azulenyl]oxy]pentanoic acid,
O-[9,10-dimethoxy1,2,3,4,5,6-hexahydro4-[(4,5,6,7,-tetrahydro 1H-1,3-diazepin-2-yl)hydrazono]8-benz(e)-azulenyl]N-[(phenylmethoxy)carbonyl]DL-homoserine,
O-[9,10-dimethoxy1,2,3,4,5,6-hexahydro4-[(3a,4,5,6,7,7a-hexahydro 1H-benzimidazol-2-yl)hydrazono]8-benz(e)azulenyl]N-[(phenylmethoxy)carbonyl]DL-homoserine.
Also a subject of the invention is a preparation process for the compounds of general formula (I) characterized in that a compound of formula (II): 
in which R2, R3, R4 and R5 are as described previously with the exception of the hydroxyl value, is subjected either to the action of a compound of formula (F1) in the presence of a base,
Hal-[A]xe2x80x94[B]xe2x80x94COR6xe2x80x83xe2x80x83(F1)
or a compound of formula (Fxe2x80x21) in the presence of a phosphine and of diethyl azodicarboxylate:
HOxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6xe2x80x83xe2x80x83(Fxe2x80x21)
in which Hal is a halogen atom, [A], [B] and R6 are as described previously, [B] also being able to represent the 
group, P being a protective group of the amine function, in order to obtain a compound of formula (IIIa): 
or to the action of an activating group then of a compound of formula (F2) in the presence of a catalyst: 
in order to obtain a compound of formula (IIIb): 
which compounds of formula (IIIa) or (IIIb) are subjected to the action of a compound of formula (F3):
H2Nxe2x80x94Gxe2x80x83xe2x80x83(F3)
in which G is as described previously, in order to obtain the compounds of formula (IVa) and (IVb) corresponding to certain products of formula (I): 
which are subjected, if appropriate, in a suitable order,
to the action of a base or an acid in order to cleave the ester and to obtain the corresponding acid,
to the action of a reducing agent suitable for partially or totally reducing the unsaturations of the R1 group,
to the action of a hydration agent of the triple bond,
to the action of a dealkylation agent,
to the action of a deprotection agent of the NHxe2x80x94P function in beta position of COxe2x80x94R6 when [B] represents the CHxe2x80x94NHP group,
to the formation of the NHxe2x80x94SO2Rc, NHxe2x80x94CO2Rc, NHCORc, NHxe2x80x94SO2xe2x80x94NHxe2x80x94Rc, NHxe2x80x94COxe2x80x94NHRc group from the corresponding amine in beta position of COR6, in order to obtain the corresponding compounds of formula (I) which are subjected if appropriate to the action of an acid or a base in order to obtain the corresponding salts or to the action of an esterification agent in order to obtain the corresponding esters.
The action of the compound of formula Hal-[A]xe2x80x94[B]xe2x80x94COR6 (F1) is preferably carried out in the presence of a mineral base such as potassium carbonate or sodium carbonate in the presence of an aprotic dipolar solvent such as dimethylformamide. Hal is preferably a chlorine or bromine atom.
The action of the compound of formula HOxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6 (Fxe2x80x21) is carried out in the presence of a phosphine such as triphenylphosphine and of an agent such as diethyl azodicarboxylate (DEAD) in an aprotic solvent such as methylene chloride.
The action of the compound of formula Hxe2x80x94Cxe2x89xa1Cxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6 (F2) is preceded by that of an activating group such as triflic anhydride of formula (CF3SO2)2O in the presence of a base such as pyridine in order to form the corresponding triflate of formula (OSO2CF3) then carried out in the presence of a palladium derivative (Pd0) such as Pd(PPh3)4.
The action of NH2xe2x80x94G (F3) is carried out, either without solvent, or in an alcoholic solvent such as ethanol or butanol. The synthon NH2xe2x80x94G is optionally used in the form of a salt such as the hydrochloride or the hydrobromide.
The saponification reaction of the ester function is carried out for example by the action of an alkaline base such as soda or potash in tetrahydrofuran or a lower alcohol such as methanol or ethanol. The ester can also be cleaved in an acid medium according to methods known by a man skilled in the art.
The reduction of the unsaturations can be carried out either totally by the action of hydrogen in the presence of a catalyst such palladium on charcoal or a rhodium catalyst such as Wilkinson""s reagent or partially (alkynylene becomes alkenylene) by the action of a poisoned catalyst such as palladium on barium sulphate poisoned with pyridine or triethylamine.
The hydration reaction allowing a xe2x80x94CH2COxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6 group to be obtained from xe2x80x94Cxe2x89xa1Cxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6 is preferably carried out by the action of water in the presence of mercury sulphate.
The dealkylation reaction allowing the products of formula (I) with R2, R3, R4 or R5 representing hydroxyls to be obtained is carried out in the presence of aluminium chloride or boron tribromide.
The functionalization of NH2 in alpha position of COR6, [B] representing CHxe2x80x94NH2 or CHxe2x80x94NH2, HCl, is carried out according to standard methods known in organic chemistry.
The formation of NHSO2Rc from the corresponding amine is preferably carried out by the action of RcSO2Hal in the presence of a base for example triethylamine.
The formation of NHCO2Rc from the corresponding amine is preferably carried out by the action of RcOH according to the method described in J. Org. Chem., 61, 3929-3934 after having previously reacted the triphosgene in the presence of sodium bicarbonate in order to intermediately obtain the isocyanate.
The salification reactions can be carried out under the usual conditions. For example, in order to salify the terminal CO2H group of R1, the operation is carried out in the presence of a sodium salt such as sodium carbonate or sodium or potassium acid carbonate.
Similarly, the salification of the amine or of the aminoguanidine which can be represented by G, by an acid, is carried out under the usual conditions. The operation is carried out for example with hydrochloric acid, for example in an ethereal solution.
The optional esterification of the products is carried out under standard conditions known to a man skilled in the art.
The operation is generally carried out by reacting the acid of formula (I) or a functional derivative with a reagent capable of. introducing the ester group a non-exhaustive list of which is given above in the definition of R6.
The products of general formulae (F1), (Fxe2x80x21), (F2), (F3) are known or prepared according to methods known to a man skilled in the art.
The grafting order of the different reagents can also be reversed, namely the compound of formula (II) is subjected to the action of a compound of formula F3 in order to intermediately obtain the product of formula (IIIc): 
which is subjected to the action of a compound of formula (F1), (Fxe2x80x21) or (F2) in order to obtain the corresponding products of formulae (IVa) and (IVb).
In this case, it may be necessary to provide protection of the G group of the product of formula (IIIc) then, after introduction of (F1), (Fxe2x80x21) or (F2), deprotection according to the methods known to a man skilled in the art (T. W. GREENE Protective Groups in Organic Synthesis. John Wiley and Sons Inc. 1991).
The deprotection reaction of the NHxe2x80x94P group in beta position of COxe2x80x94R6, [B] representing the CHxe2x80x94NHP group, is also carried out according to methods known to a man skilled in the art, in particular when P represents the CO2tBu group, by a decarboxylation reaction such as for example by the action of hydrochloric acid.
Bone is constantly subjected to a dynamic process which includes bone resorption and bone formation. These processes are mediated via specialized cells. Bone formation is the result of the deposit of a mineral matrix by osteoblasts and bone resorption is the result of the dissolution of this bone matrix by osteoclasts. Osteoporosis is characterized by a dry loss of this bone matrix. An activated mature osteoclast resorbs bone after adherence to the bone matrix by the secretion of proteolytic enzymes, and protons inside the adherence zone, resulting in depressions or holes in the surface of the bone which appear at the moment when the osteoclast detaches itself from the bone.
The compounds of formula (I) as well as their pharmaceutically acceptable addition salts have useful pharmacological properties. These compounds inhibit bone resorption which is mediated via the osteoclasts.
The compounds of the invention are therefore useful in the treatment of illnesses caused by loss of bone matrix, in particular osteoporosis, malignant hypercalcemia, osteopenia due to bone metastases, periodontitis, hyperparathyroidism, periarticular erosions in rhumatoid arthritis, Paget""s disease, osteopenia induced by immobilization, glucocorticoid treatments or deficiencies in male or female sex hormones.
They can also be used for the treatment of inflammatory, cancerous and cardiovascular disorders including atherosclerosis, recurrence of stenosis.
They can finally be used as angiogenesis inhibitors and therefore in the treatment of tumours, by inhibition of their neovascularization, diabetic retinopathies and nephropathies.
Recent studies have shown that the fixing of the osteoclast to the bone is mediated by receptors: the integrins.
The integrins are a superfamily of receptors mediating the cell/cell and more particularly cell/matrix adherence processes, including in particular xcex12bxcex23 as a blood platelet receptor (fibrinogen) and xcex1vxcex23 as a receptor of vitronectin, and of bone sialoproteins such as osteopontin and thrombospondin.
These receptors which are protein heterodimers composed of two sub units xcex1 and xcex2, possess fixation sites for divalent ions such as Ca2+ in particular and a recognition site for their ligand predefined by the quality of their sub units.
The xcex1vxcex23 receptor is a transmembrane glycoprotein which is expressed in a large number of cells including endothelial cells, smooth muscle cells, osteoclasts and cancerous cells which therefore bings about a pluripotentiality of the compounds according to the invention.
The xcex1vxcex23 receptors expressed on the membrane of osteoclasts are the basis of the adherence/resorption process, contribute to the organization of the cellular cytoskeleton, and are implicated in osteoporosis (Ross et al., J. Biol. Chem., 1987, 262, 7703).
The xcex1vxcex23 receptors expressed in the cells of the smooth muscle of the aorta stimulate their migration towards the neointima, which brings about the formation of atherosclerosis and the post-angioplastic reccurrence of stenosis (Brown et al, cardiovascular Res. (1994), 28, 1815).
The endothelial cells secrete growth factors which are mitogenic for the endothelium and can contribute to the formation of new blood vessels (angiogenesis). Angiogenic stimulation causes the formation of new blood vessels. Antagonists of the integrin xcex1vxcex23 can therefore bring about a regression in cancerous tumours by inducing apoptosis of the angiogenic blood vessels. (Brook et al. Cell (1994) 79, 1157).
The natural ligands of the integrin xcex1vxcex23 all contain the RGD unit (Arg-Gly-Asp). The peptides containing this RGD unit as well as anti xcex1vxcex23 antibodies are known for their ability to inhibit the resorption of dentine, to prevent the adherence of the osteoclasts on the mineralized matrices (Horton et al. Exp. Cell. Res. (1991), 195, 368).
The peptide echistatin isolated from snake venom also containing an RGD unit is described as an inhibitor of the adherence of osteoclasts to bone, and is therefore a powerful inhibitor of bone resorption in tissues cultured in vitro (Sato et al. J. Cell. Biol. (1990), 111, 1713) and in vivo in a rat (Fisher et al. Endocrinology (1993), 132, 1441).
The compounds of formula (I) as well as their pharmaceutically acceptable addition salts and their esters may possess in particular an affinity vis-à-vis the vitronectin receptor xcex1vxcex23 or vis-à-vis other integrins having vitronectin as ligand (xcex1vxcex21, xcex1vxcex25, xcex12bxcex23) by inhibiting binding to their natural ligand.
This property therefore makes the compounds of the invention useful for the prevention or the treatment of illnesses the underlying pathology of which is caused by the ligands or cells which interact with the vitronectin receptor.
These compounds can also possess an activity vis-à-vis other integrins which interact with their ligand via the RGD tripeptide sequence, conferring them with pharmacological properties which can be used to treat pathologies associated with these receptors.
This activity vis-à-vis integrins therefore makes the compounds of the invention of use in the treatment of many illnesses such as those mentioned above or in the review by Dermot Cox DNandP 8(4) May 1995, 197-205 the content of which is integrated into the present Application.
A subject of the invention is therefore the compounds of formula (I) as medicaments, as well as their pharmaceutically acceptable addition salts and their esters.
Among the medicaments of the invention, there can be mentioned in particular the compounds described in the experimental part.
Among these products, a more particular subject of the invention is, as medicaments, the compounds of formula (I) listed previously.
The dosage varies according to the illness to be treated and the administration route: it can vary for example from 1 mg to 1000 mg per day for an adult by oral route.
The invention extends to the pharmaceutical compositions containing as active ingredient at least one medicament as defined above.
The compounds of formula (I) are used by digestive, parenteral or local route, for example by percutaneous route. They can be prescribed in the form of plain or sugar-coated tablets, capsules, granules, suppositories, pessaries, injectable preparations, ointments, creams, gels, microbeads, nanobeads, implants, patches, which are prepared according to the usual methods.
The active ingredient or ingredients can be incorporated with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
The products of formula (II), in which the hydroxy radical hydroxy is in position 10, R2 in position 8 and R3 in position 9, represent an O-(Alk) or Oxe2x80x94(CH2)0-3-Ar group, R4 and R5 are hydrogen atoms, are prepared according to the method described in the European Patent Application No. 0729933 and in the experimental part hereafter (Preparation 2).
The two other position isomers can be prepared in the following manner:
A compound of formula (IIA): 
is subjected to the action of an alkylation reagent, in order to obtain the compound of formula (IIB): 
which compound of formula (IIB) is subjected: either to the action of a protection reagent of the diols in a basic medium, in order to selectively obtain the product of formula (IIC): 
in which P represents the remainder of a protection reagent of the diols, which is successively subjected to the action of a protection reagent of the phenol, a deprotection reagent of the diols, an alkylation agent then a deprotection agent of the phenol in order to obtain the compound of formula (IID) corresponding to the trisubstituted product of formula (II) with OH in position 8: 
or to the successive action of a protection agent of the phenol, an alkylation agent then a deprotection agent in order to obtain the compound of formula (IIE) corresponding to the trisubstituted product of formula (II) with OH in position 9: 
By dealkylation reagent is preferably meant agents such as boron tribromide or aluminium chloride.
The protection reagent of the diols which is reacted on the products of formula (IIB) can be a boron derivative such as boric acid, a trialkyl borate, for example a trimethyl or triethyl borate, or also borax.
By protection agent of the phenol is meant in particular a halide such as mesyl or tosyl chloride or bromide or also a benzylated derivative such as benzyl tosylate or mesylate.
By deprotection reagent of the diols is meant in particular a strong acid such as hydrochloric acid, sulphuric acid or paratoluene sulphonic acid or also an oxidizing agent, for example hydrogen peroxide, in the case of a protection by a boron derivative.
By alkylation agent is meant any standard agent known to a man skilled in the art for alkylating the phenols. There can be mentioned for example an alkyl halide such as methyl or ethyl chloride, an alkyl sulphate such as methyl or ethyl sulphate or also diazomethane.
By deprotection agent is meant a base such as soda, potash or also sodium or potassium carbonate.
The monosubstituted products of formula (II), in which R2, R3, R4 and R5 represent a hydrogen atom, are prepared according to an analogous method to that described in the European Patent Application No. 0729933:
(i) A compound of formula (a): 
xe2x80x83in which O-(Alk) is in meta or para position of the alkylcarboxylic group, (Alk) being as defined previously, is subjected to the action of a halogenation agent in order to obtain the corresponding acyl halide,
(ii) Which is subjected to the action of a reagent of formula (b): 
xe2x80x83in which R(I) and R(II), identical or different, represent an alkyl group containing 1 to 6 carbon atoms, or R(I) and R(II) together with the nitrogen atom to which they are linked, represent a saturated or unsaturated heterocycle with 5 or 6 members optionally containing another heteroatom chosen from O and N,
in Order to Obtain a Compound of Formula (c): 
(iii) which is subjected to the action of a halogenation agent in order to obtain a compound of formula (d): 
xe2x80x83in which Hal1 represents a halogen atom,
(iv) which is subjected to the action of a Lewis acid, in order to obtain a compound of formula (e): 
(v) which is subjected to a dealkylation reagent in order to obtain the product of formula (IIF) corresponding to the expected mronosubstituted product of formula (II): 
The disubstituted products of formula (II), in which R2 represents O-(Alk) or Oxe2x80x94(CH2)0-3xe2x80x94Ar, R3, R4 and R5 are hydrogen atoms and OH and R2 being in position 8, 9 or 10, are prepared according to the method as described above starting from the compound of formula (axe2x80x2): 
in which O-(Alk) and R2 are in meta or para position of the alkyl carboxylic group, R2 being an O-(Alk) or xe2x80x94(CH2)0-3xe2x80x94Ar group, which is successively subjected to reactions (i), (ii), (iii), (iv) and (v) and the products of formula (IIG) are obtained corresponding to the expected bisubstituted products of formula (II): 
The halogenation agent which is reacted on the compound of formula (a) or (axe2x80x2) is for example thionyl chloride, oxalyl chloride or any other agent known to a man skilled in the art for preparing an acid halide.
The reagent of formula (b) is prepared starting from cyclopentanone and a secondary amine, for example diethylamine, piperidine, piperazine or, preferably, morpholine. The operation is carried out in the presence of a strong acid catalyst, for example paratoluene sulphonic acid.
The action of the enamine of formula (b) on the acid halide is preferably carried out in the presence of a tertiary amine such as triethylamine or pyridine.
The halogenation agent which is reacted on the compound of formula (c), or its disubstituted equivalent of formula (cxe2x80x2), can be for example thionyl chloride, phosgene, phosphorus oxychloride or, preferably, oxalyl chloride.
The Lewis acid used for cyclizing the compound of formula (d), or its disubstituted equivalent of formula (dxe2x80x2) is for example aluminium chloride, titanium tetrachloride, or preferably ferric chloride, or tin tetrachloride. The reaction, like the preceding ones, can be carried out, for example, in a halogenated solvent such as methylene chloride, chloroform or dichloroethane.
The dealkylation reagent of the compound of formula (e), or its disubstituted equivalent of formula (exe2x80x2) in order to obtain the corresponding phenols is preferably aluminium chloride or boron tribromide.
The products of formula (II) in which R4 is different from the hydrogen atom are prepared by standard methods of aromatic electrophilic and nucleophilic substitution known to a man skilled in the art.
The products of formula (II) in which R5 is different from the hydrogen atom are prepared according to methods known to a man skilled in the art and in particular according to the method described in the European Patent Application No. 0729933, that is to say by halogenation then the action of water or a suitable alcohol.
The products of formula (II) in which R5 is a hydrogen atom and in which there is a double bond in position 1-2 are prepared according to methods known to a man skilled in the art and in particular according to the method described in the European Patent Application No. 0729933, that is to say by dehydration or dealkoxylation in anhydrous acid medium.
The products of formula (II) in which the junction between the ring in position 5 and the ring in position 7 is saturated are prepared according to standard hydrogenation methods in particular in the presence of palladium on charcoal of the corresponding double bond.
The introduction of R4, R5 as well as the hydrogenation reaction is preferably carried out on the compounds of formula (IIA), (IID), (IIE), (IIF) or (IIG).
The products of formula (II) in which R2 and R3, each in ortho position, form a ring of xe2x80x94Oxe2x80x94(CRdRe)nxe2x80x94O type as defined previously, are also prepared according to methods known to a man skilled in the art and in particular according to the method described hereafter in the experimental part.
A subject of the invention is also, as intermediate products, the products of formulae (IIIa), (IIIb), (IIIc) and (II), it being understood that the compounds of formula (IIc) and the following compounds:
2,3,5,6-tetrahydro-9,10-dimethoxy-8-hydroxy-benz[e]azulen-41H)-one, and
2,3,5,6-tetrahydro-8,9-dimethoxy-10-hydroxy-benz[e]azulen-4(1H)-one,
are excluded. The preparation of these 2 compounds appears hereafter in the experimental part.